Type 1 diabetes is an autoimmune disease characterized by destruction of insulin-secreting pancreatic islet β cells by pathogenic autoreactive T cells (Castano 1990; Rossini 2004). The resultant decrease in insulin secretion leads to hyperglycemia. Type 1 diabetes has traditionally been managed by administering exogenous insulin, which delays the onset and progression of the microvascular complications associated with diabetes. However, insulin administration does not cure the disease. A more recently developed therapy is islet transplantation, in which faulty pancreatic islets are replaced with new insulin-producing islets. However, the underlying autoimmune disorder remains, meaning that the newly transplanted islets will continue to be attacked by the host immune system. This can be overcome using long-term immunosuppressive therapy, but this procedure is accompanied by a variety of deleterious side effects.
An alternative to immunosuppressive therapy is bone marrow transplantation (BMT), in which bone marrow from a non-autoimmune donor is transferred to the autoimmune host, leading to allogeneic hematopoietic chimerism. In a mouse model, BMT has been shown to reverse insulitis, prevent the development of diabetes, and induce tolerance to donor islet cells (Li 1996; Kaufman 1997; Seung 2000; Beilhack 2003; Nikolic 2004). However, BMT has several potential drawbacks. First, it requires conditioning of the host by non-myeloablative total body irradiation (TBI) (Li 1996; Kaufman 1997; Seung 2000; Beilhack 2003; Nikolic 2004), which is highly toxic. Second, it is often accompanied by the development of acute and chronic graft-versus-host disease (GVHD) (Exner 1997; Sullivan 1997; Burt 1998; Wagner 1998). The toxicity of TBI conditioning and the potential for GVHD have limited the application of BMT for the treatment of type 1 diabetes and the induction of immune tolerance to islet transplantation (Ricordi 2003). Administration of co-stimulatory blockade (anti-CD40L) has been reported to induce mixed chimerism in non-autoimmune mice (Wekerle 2000; Seung 2003). However, there is a need in the art for a radiation-free BMT regimen for the treatment of autoimmunity and induction of donor tolerance.